FI90766B - Process for the preparation of pharmaceutically active 4- (2,6,6-trimethyl-cyclohex-1-enyl) -but-3-ene-1-ynyl-substituted compounds - Google Patents

Abstract

Retinoid-like activity is exhibited by compounds of the formula <CHEM> wherein A is pyridyl, furyl, thienyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-5; and B is H, -COOH and its esters, amides and pharmaceutically acceptable salts, -CHO and its acetal derivatives, -COR1 and its ketal derivatives where R1 is -(CH2)nCH3 where n is defined above, or -CH2OH and its ether and acyl ester derivatives; or a pharmaceutically acceptable salt.

Description

90766

Process for the preparation of pharmaceutically active 4- (2,6,6-trimethyl-cyclohex-1-enyl) -but-3-en-1-ynyl-substituted compounds

The present invention relates to a process for the preparation of novel compounds having retinoic acid-like activity. More specifically, the present invention relates to a process for the preparation of compounds in which three olefin units of a retinoic acid-containing terminal unit have been replaced by an ethynylheteroaromatic group. Such modifications of the structure of retinoic acid have retinoic acid-like activity.

The filamentous compounds disclosed in JP Patent 56-123903 have the structure 2- (2 - ((1,1-dimethyl) dimethylsilyl) oxy) ethyl-alpha- (4- (2,6,6-trimethyl- 1-cyclohexen-l-yl) -3-buten-l-ynyl) -1-cyclopentene-l-methanol. This compound uses the 1- (2 ', 6', 6'-trimethylcyclohex-1'-enyl) -but-1-en-3-yne portion of the compounds disclosed in the present invention. However, that fragment is the only similarity between the compounds of the Japanese publication and those of the present invention. Such compounds are not within the scope of the present invention.

The present invention relates to a process for the preparation of a pharmaceutically active 4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl-substituted compound of the formula

A-B I

öc * wherein A is pyridyl, furyl or thienyl; and B is -COOH or a pharmaceutically acceptable salt thereof, or a lower alkyl ester thereof, -CHO, a lower alkylalkoxymethyl, 1-2 hydroxy-lower alkyl tax lower alkylcarbonyloxymethyl.

The compounds of formula I can be used for the treatment of skin diseases such as acne, Darier's disease, psoriasis, scabies, eczema, atopic dermatitis and epithelial cancers. These compounds are also useful in the treatment of joint diseases and other immunological disorders (e.g., lupus erythematosus), in promoting wound healing, and in the treatment of dry eye symptoms.

Compounds of formula I according to the invention may be prepared by reacting the following compound of formula II with the following compound of formula III in the presence of Pd (PQ3) 4 (Q is phenyl) or a similar complex

X ^^ - ^ ZnCl X-A-B

II III

wherein in formula III A is as defined above, X is halogen, preferably iodine, and B is a protected carboxylic acid, alcohol or aldehyde to give a compound of formula I and optionally converting the resulting compound of formula I to another compound of formula I.

According to one embodiment of the invention, the acid of the formula I is converted into a lower alkyl ester or the acid is reduced to hydroxymethyl or aldehyde or the hydroxymethyl is converted to the former alkylcarbonyloxymethyl or the hydroxymethyl is oxidized to the aldehyde or the aldehyde is converted to acetal

As used herein and otherwise in connection with the present invention, lower alkyl means a compound having 1 to 6 carbon atoms.

Il 90766 3

A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not cause any adverse or unpleasant effect in the subject to whom it is administered.

Pharmaceutically acceptable salts may be derived from organic or inorganic acids or bases. The salt may be a mono- or polyvalent ion. Of particular interest are inorganic ions, sodium, potassium, calcium and magnesium. Organic salts can be prepared with amines, especially ammonium salts such as mono-, di- and trialkylamines or ethanolamines. Salts can also be formed with caffeine, tromethamine and the like molecules.

Preferred compounds of the present invention are those in which the ethynyl group and the B group are attached at the 2- and 5-positions of the pyridine ring, respectively (positions 6- and 3 in the nicotinic acid nomenclature are equivalent to the 2/5 notation used in the pyridine nomenclature) or in the thiophene group in the 5- and 2-positions, respectively, and B is -C00H, an alkali metal salt or an organic amine salt or a lower alkyl ester or -CH2OH or a lower alkyl ester thereof, i.e. lower alkylcarbonyloxymethyl. More preferred compounds are: 6- [4- (2,6,6-Trimethyl-cyclohex-1-enyl) -but-3-en-1-ynyl] -nicotinic acid ethyl ester; 6- [4- (2,6,6-trimethylcyclohex-l-enyl) -but-3-en-l-ynyl-phenyl] -nikotiinihappc; 5- [4- (2,6,6-Trimethyl-cyclohex-1-enyl) -but-3-en-1-ynyl] -thiophene-2-carboxylic acid ethyl ester; and 5- [4- (2,6,6, -trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] thiophene-2-carboxylic acid.

4

The compounds of the present invention may be administered systemically or topically, depending on factors such as the condition being treated, the need for treatment specific to a particular subject, the amount of drug to be administered, and many other factors.

In the treatment of skin diseases, it is generally advantageous to administer the drug topically, although in certain cases, such as in the treatment of vesicular acne, oral administration may also be used.

For topical treatment, any conventional topical formulation can be used, such as a solution, suspension, gel, ointment or ointment, etc. Such topical formulations are well known and are fully described and described in the pharmaceutical formulation literature, such as Remington's Pharmaceutical Science. 17th Edition, Mack Publishing Company, Easton, Pennsylvania. For topical administration, these compounds could also be administered as a powder or spray, especially in the form of an aerosol.

If the drug is to be administered systemically, it can be prepared as a powder pill, tablet, etc., or a syrup or elixir for oral administration. For intravenous or intraperitoneal administration, the compound is prepared as a solution or suspension which can be administered by injection. In certain cases, it will be useful to formulate these compounds in the form of a suppository or a sustained release formulation, a subcutaneous formulation or an intramuscular injection.

Other drugs may be added to the topical formulation for secondary purposes, such as to treat dry skin, to provide protection against light; other dermatological drugs can be added to prevent infection, reduce irritation, inflammation, and the like.

90766 5

Treatment of skin diseases or other symptoms known or found to be sensitive to treatment with retinoic acid can be accomplished by administering a therapeutically effective dose of one or more compounds of the present invention. The therapeutic concentration will be that concentration that alleviates a particular condition or slows the deterioration of the condition. In certain cases, the drug could be used in a prophylactic manner to prevent the onset of a particular condition. The therapeutic concentration to be administered will vary from condition to condition and, in certain cases, may vary with the severity of the condition being treated and the sensitivity of the patient to the particular treatment. Thus, a particular therapeutic concentration is best determined by routine experimentation, as appropriate.

For example, in the treatment of acne or other skin diseases, a formulation containing 0.01 to 1.0 mg of active ingredient per milliliter of formulation is expected to form a therapeutically effective concentration. When administered systemically, an amount of 0.01 to 5 mg per kilogram of body weight per day is expected to produce a therapeutic result.

The retinoic acid-like activity of these compounds was confirmed by a classical method of measuring retinoic acid activity, which is coupled with the effects of retinoic acid on omitinin carboxylase. The original work on the correlation between retinoic acid and the reduction in cell division was done by Verma & Boutwell, Cancer Research, 1977, 22 »2196-2201. According to this reference, the activity of ornithine decarboxylase (ODC) increases before polyamine biosynthesis. On the other hand, it has been found that an increase in polyamine synthesis may correlate with or be coupled to cell division. Thus, if ODC activity could be inhibited, excessive cell division could be modulated. Although the reasons for the increase in ODC activity are unknown, it is known that 12-O-tetradecanoyl phorbol 13-acetate (TPA) provides 6 ODC activity. Retinoic acid inhibits the induction of this TPA-induced ODC activity. The compounds of the present invention also inhibit the induction of ODC by TPA, as illustrated by an assay that essentially follows the method set forth in Cancer Res .: 1662-1670, 1975.

It is expected that the compounds of the present invention can be prepared using a variety of synthetic routes. To illustrate the present invention, a series of steps used to obtain certain representative compounds of formula I are shown in Scheme I. It will be apparent to the synthesis that the conditions set forth in the present application are specific embodiments that can be generalized to all compounds of formula I. . Reaction Scheme I shows a general procedure for the preparation of compounds of formula I.

Scheme I

δο ^ - ör “- öc ^“ 1 2 3

Halogen-substituted heterocyclic esters / f

. A-B

oof

Alcohols Acids, Esters, Salts

f A-B

esters

Aldehydes --- Acetals

II

90766 7 In this scheme, halogen in "halogen-substituted heterocyclic esters" may be Br, Cl or I, but Br and I are preferred. A: 11a and B have the same meaning as given above in connection with the definition of the substituents of formula I.

Generally speaking, the acetylene group is attached by treating the ketone of formula 1 with a strong base and dialkyl chlorophosphate, followed by treating it again with a base. Then, by converting the acetylene group to a heavy metal salt, the ZnCl salt, the addition of an acetylene group to the aromatic ring can be achieved. Due to the basic nature of this ZnCl salt, the acidic properties of group B must be minimized. The formation of derivatives from acids, alcohols and aldehydes is necessary to optimize the reaction yield.

The compound of formula 1 is sold by Aldrich Chemical Company as Beta-Ionone. The ketone is converted to a triple bond under reduced pressure in an inert atmosphere by means of lithium diisopropylamide (LDA) or a similar base. The reaction is carried out in an ether-type solvent such as a dialkyl ether or a cyclic ether such as tetrahydrofuran, pyran and the like.

More specifically, lithium diisopropylamide is developed in situ by stirring diisopropylamine in a dry solvent such as tetrahydrofuran, which is then cooled to between -70 ° and -50 ° C under an inert atmosphere. An equimolar amount of an alkyllithium compound, such as n-butyllithium, in a suitable solvent is then added at a reduced temperature, and the mixture is stirred for an appropriate time to form lithium diisopropylamide (LDA). The ketone of formula 1 (in at least a 10% molar excess) is dissolved in the solvent of the reaction mixture, the solution is cooled to the temperature of the LDA mixture and added to this solution. After brief stirring, the solution is treated with dialkyl chlorophosphate, preferably diethyl chlorophosphate, which is used in a molar excess of about 20%. The temperature of the reaction mixture is gradually brought to room temperature. This solution is then added to a second solution of lithium diisopropylamide prepared in situ using a dry solvent and under an inert atmosphere, preferably argon, under reduced pressure (-78 ° C). The reaction mixture is then warmed again to room temperature where it is stirred for a relatively long time, preferably 10-20 hours, more preferably about 15 hours. The solution is then acidified and the product is recovered by conventional separation methods.

The compound of formula 3 is prepared under conditions free of water and oxygen. As the solvent, a dry, ether-type solvent such as a dialkyl ether or a cyclic ether such as furan or pyran, especially tetrahydrofuran, can be used. The solution of formula 2 is first prepared in an inert atmosphere such as argon or nitrogen, and then a strong base such as n-butyllithium (in a molar excess of about 10%) is added. This reaction is initially allowed to proceed at a low temperature between -10 ° C and + 10 ° C, preferably at about 0 ° C. The reaction mixture is stirred for a short time, 30 minutes to 2 hours, and then treated with about a 10% molar excess of molten zinc chloride dissolved in the solvent of the reaction mixture. This mixture is stirred for an additional 1-3 hours at approximately the initial temperature, and then the temperature is raised to about ambient temperature for 10-40 minutes.

Halogen-substituted heterocyclic esters are prepared from the corresponding acids, in which case the halogen is Cl, Br or I.

These pyridyl, furyl and thienyl acids are all available from chemical manufacturers, or can be prepared by published methods. The esterification is carried out by refluxing the acid in a solution of a suitable alcohol in the presence of thionyl chloride, or by reacting the acid and the alcohol 907669 in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester is recovered and purified by conventional methods. Other conventional methods for effecting esterification may also be used.

To form a compound of formula 4, the alkyl halofuranoate or the corresponding alkyl halo ester of thiophene or pyridine is dissolved in a dry solvent. The ester is used in an amount approximately equal to the molar amount of the starting material of compound 3. This solution is introduced into a suspension of tetrakis (triphenylphosphine) palladium (about 5-10% molar amount of reactants) in the solvent of the reaction mixture at a temperature of about -10 ° to + 10 ° C. This mixture is stirred for a short time, about 15 minutes. To this freshly prepared solution is then added a preformed solution of compound 3, zinc chloride disalt, and the additions are made at room temperature. This solution is stirred for an extended period of time, about 15 to 25 hours, at room temperature. The reaction is then quenched with acid and the product is isolated and purified by conventional means to give compounds of formula 4.

Alcohols are prepared by converting the corresponding acids to acid chlorides with thionyl chloride or otherwise (J. March, Advanced Organic Chemistry, Second Edition, McGraw-Book Company), then reducing the acid chloride with sodium borohydride (March, same publication, page 1124) to give the corresponding acids. alcohols. Alternatively, the esters can be reduced with lithium aluminum hydride at reduced temperatures.

Aldehydes can be prepared from the corresponding primary alcohols using weak oxidants, such as using pyridinium dichromate in methylene chloride (Corey, EJ, Schmidt, G., Tet. Lett., 399, 1979) or dimethyl sulfoxide / oxalyl chloride in methylene chloride (Dura, K. Tetrahedron, 1978, 24, 1651).

10

Acetals can be prepared from the appropriate aldehyde by the method described by March in the aforementioned publication, page 810.

The following examples are presented to illustrate the invention, not to limit its scope.

Example 1 1- (2,6,6-Trimethylcyclohex-1-enyl) but-1-en-3-one

A solution of 12.17 g (120.27 mmol) of diisopropylamine in 200 mL of dry tetrahydrofuran was cooled to -78 ° C under argon and treated dropwise with a syringe over 75 mL. 1.6 molar (120 mmol) n-butyllithium prepared in hexane. This mixture was stirred at about -78 ° C for one hour and then treated via tube by adding a cooled (-78 ° C) solution of 21.99 g (114.35 mmol) of beta-ionone (1) which was in 20 ml of dry tetrahydrofuran. This mixture was treated at about -78 ° C for one hour, treated with 21.73 g (125.93 mmol) of diethyl chlorophosphate, and allowed to warm to room temperature over 2 hours. This solution was then transferred via tube to a solution of lithium diisopropylamide prepared by stirring under argon a solution of 26.57 g (262.57 mmol) of diisopropylamine in 150 mL of dry tetrahydrofuran and 164 mL of 1.6- molar (262.4 mmol) n-butyllithium in hexane for 0.5 h at -78 ° C. The mixture was allowed to warm to room temperature, stirred for 15 hours, acidified with 250 mL of 3N HCl, and extracted with pentane. The organic extract was washed with 1N HCl, water, saturated NaHCO 3 and saturated NaCl and dried (MgSO 4). The product was concentrated and distilled using a ball condenser (50 ° C; 0.1 mm) to give the title compound as a colorless oil. PMR (CDCl 3): δ 1.0 (20 ^, s), 1.45 (2H, m), 1.65 (CH 3, s), 1.92 (2H, m), 2.85 (1H, d , 90766 11 J ~ 3Hz), 5.35 (1H, dd, J ~ 16Hz, 3Hz), 6.6 (1H, d, J ~ 16Hz). Example 2 6-Chloro-nicotinic acid ethyl ester

A mixture of 15.75 g (0.1 mol) of 6-chloronicotinic acid, 6.9 g (0.15 mol) of ethanol, 22.7 g (0.11 mol) of dicyclohexylcarbodiimide and 3, 7 g of dimethylaminopyridine, (0.03 mol) in 200 ml of methylene chloride, was refluxed for 2 hours. The mixture was allowed to cool, the solvent was removed in vacuo and the residue was subjected to flash chromatography to give 16.7 g of the title compound as a low melting white solid. PMR (CDCl 3): δ 1.44 (3H, t, J ~ 6.2Hz), 4.44 (2H, q, J ~ 4.4Hz), 7.44 (1H, d, J ~ 8.1Hz) ), 8.27 (1H, dd, J ~ 8.1 Hz, 3Hz), 9.02 (1H, d, J ~ 3Hz).

Example 3 6- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-phenyl] nicotinic acid ethyl ester The reaction vessels used in this method were dried in a flame under vacuum, and all operations were performed under an oxygen-free argon or nitrogen atmosphere. To a solution of the compound of Example 1 (620.7 mg (3.5614 mmol) in 4 mL of dry tetrahydrofuran at 0 ° C was added dropwise 2.25 mL of 1.6 M (3.6 mmol) n- This mixture was stirred at 0 ° C for 10 minutes, at room temperature for 10 minutes, and the mixture was again cooled to 0 ° C. A solution of 500 mg (3.6689 mmol) of melted melt was added via conduit to the cooled mixture. zinc chloride in 4 ml of dry tetrahydrofuran with stirring at 0 ° C for one hour and at room temperature for 10 minutes A solution of 664 mg (3.5774 mmol) of 6-chloronicotinic acid ethyl ester in 4 ml of dry tetrahydrofuran was transferred via tube to a suspension containing 12,430 mg (0.3721 mmol) of tetrakis (triphenylphosphine) palladium in 6 ml of dry tetrahydrofuran, and stirred for 10 minutes, this mixture was then treated via tube with a solution of alkynyl zinc and the resulting the mixture was stirred at room temperature for 60 hours. Water (100 ml) was added and the products were extracted with 3 x 100 ml of ether. The combined ether extracts were washed with saturated NaCl solution, dried (MgSO 4) and concentrated to give a brown oil. This oil was purified by flash chromatography (silica gel; 10% ethyl acetate in hexane) followed by high performance liquid chromatography (Waters 6000; Partisil M 9 10/50; 5% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR (CDCL3); δ 1.06 (2CH 2, s), 1.42 (3H, t, J 7 7 Hz), 1.46 (2H, m), 1.61 (2H, m), 1.78 (CH 3, s) 2 .05 (2H, m), 4.42 (2H, t, J 7 7 Hz), 5.75 (1H, d, J 16 16.5 Hz), 6.89 (1H, d, J 16 16.5 Hz) , 7.48 (1H, d, J ~ 7.8Hz), 8.25 (1H, dd, J ~ 7.8, 2Hz), 9.15 (1H, d, J ~ 2Hz).

Example 4 5-Bromo-2-furancarboxylic acid ethyl ester

To a stirred suspension of 8.43 g (44.14 mmol) of 5-bromo-2-furancarboxylic acid in 100 ml of absolute ethanol was added 4 ml of thionyl chloride. This mixture was refluxed for 3 hours and stirred at room temperature for 18 hours. The solvent was removed in vacuo, the residual oil was treated with 100 mL of water, and treated with 3 x 75 mL of ether. The combined ether extracts were washed with saturated NaHCO 3 and saturated NaCl solutions and dried (MgSO 4). The solvent was removed in vacuo and the residue was distilled using a ball condenser (60 ° C; 0.4 mm) to give the title compound as a colorless oil. PMR (CDCl 3); 1.35 (3H, t, J ~ 7Hz), 4.37 (2H, q, J ~ 7Hz), 6.45 (1H, d, J ~ 4Hz), 7.1 (1H, d, J ~ 4Hz) ).

Il 90766 13

Example 5 Ethyl 5-bromothiophenecarboxylic acid To 1.092 g (5.7157) of 5-bromothiophene-2-carboxaldehyde were added successively 1.507 g (30.75 mmol) of sodium cyanide, 60 ml of ethanol, 602.5 mg (10.04 mmol) and acetic acid. 10.62 g (122.16 mmol) of manganese dioxide. This mixture was stirred at room temperature for 24 hours, then filtered through diatomaceous earth and the residue washed several times with ether. The combined filtrates were concentrated, the residue was then taken up in water and extracted with 3 x 75 ml of ether. The combined ether extracts were washed with saturated NaHCO 3, saturated NaCl and dried (MgSO 4), concentrated in vacuo and distilled using a ball condenser (70 ° C; 0.1 mm) to give the title compound as a pale yellow oil. PMR (CDCl 3): δ 1.3 (3H, t, J ~ 7Hz), 4.35 (2H, t, J ~ 7Hz), 7.12 (1H, d, J ~ 4Hz), 7.6 (1H , d, J ~ 4Hz).

Example 6 5- [4- (2,6,6-Trimethyl-cyclohex-1-enyl) -but-3-en-1-ynyl] -2-furancarboxylic acid ethyl ester 5- (4- (2,6,6-trimethyl-cyclohex-1 -enyl) -but-3-enyl-thiophene-2-carboxylic acid ethyl ester

Using the procedure and conditions described in Example 3, but using 5-bromo-2-furancarboxylic acid ethyl ester prepared in Example 4 or 5-bromo-thiophene-2-carboxylic acid ethyl ester prepared in Example 5, respectively, the title compounds were prepared. . The furan carboxylic acid ethyl ester had the following properties of the PMR spectrum: PMR (CDCl 3): δ 1.1 (6H, s), 1.43 (3H, t, J ~ 7.6 Hz), 1.52 (2H, m), 1, 65 (2H, m), 1.81 (3Η, δ), 2.1 (2H, m), 4.42 (2H, q, J ~ 7.66Hz), 5.73 (1H, d, J- 16.8Hz), 6.66 (1H, d, J ~ 3.5Hz), 6.83 (1H, d, J ~ 16.8Hz), 14 7.21 (1H, d, J ~ 3.5Hz) . The ethyl ester of thiophene-2-carboxylic acid had the following PMR spectral properties: PMR (CDCl 3): δ 1.08 (6H, S), 1.39 (3H, t, J ~ 7.2Hz), 1.50 (2H , m), 1.62 (2H, m), 1.79 (3H, s), 2.08 (2H, m), 4.37 (2H, q, J 7 7.5 Hz), 5.72 ( 1H, d, J ~ 16.5Hz), 6.76 (1H, d, J ~ 16.5Hz), 7.14 (1H, d, J ~ 3.9Hz), 7.67 (1H, d, J ~ 3.9Hz).

Example 7 6- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] nicotinic acid

Nitrogen gas was bubbled immediately before use through the solutions used in the present experiment. To a stirred solution of 53 mg (0.1641 mmol) of 6- (4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] nicotinic acid ethyl ester in 200 mL ethanol, 132 ml of a 1.86 molar solution (0.245 g mmol) of KOH in ethanol and water were added under nitrogen, after stirring at room temperature for 3 hours, the solvent was removed in vacuo and the residue was treated with 1 ml of water and extracted 2x1 ml. The aqueous layer was then acidified with 50% aqueous acetic acid and extracted with 3 x 2 mL of ether The combined ether extracts were dried (MgSO 4) and concentrated in vacuo to give the title compound as a pale yellow powder PMR (CDCl 3): δ 1. 06 (6H, s), 1.48 (2H, m), 1.62 (2H, m), 1.78 (3H, s), 2.05 (2H, m), 5.75 (1H, d , J 16 16.4Hz), 6.93 (1H, d, J 16 16.4Hz), 7.55 (1H, d, J 8 8.1 Hz), 8.35 (1H, dd, J 8 8, 1.2.3 Hz), 9.29 (1H, d, J ~ 2.3Hz).

By proceeding in the same manner, the esters prepared according to Example 6 can be converted into the corresponding acid. For example: 5- [4- (2,6,6-trimethyl-cyclohex-1-enyl) -but-3-enyl] -furancarboxylic acid; and 90766 5- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] -thiophene-2-carboxylic acid.

Example 8 2- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] -5-hydroxymethylpyridinium A 250 ml three-necked flask is fitted with a stirrer, dropping funnel, line for nitrogen inlet. as well as a thermometer. A solution of 379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethyl ether is placed in the flask. The solution is cooled to -65 ° C under nitrogen and a solution of 3.2343 g (10 mmol) of 6- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-ene is added. -1-ynyl] nicotinic acid ethyl ester in 15 ml of dry ether, dropwise at such a rate that the temperature does not exceed -60 ° C. The mixture is stirred at -30 ° C for one hour, and the excess hydride is then decomposed by adding 300 mg (3.4 mmol) of ethyl acetate. The reaction mixture is then hydrolyzed by adding 3 ml of saturated ammonium chloride solution, and the temperature is allowed to rise to room temperature. The mixture is then filtered and the residue is washed with ether. The ether layer was then washed with brine, dried (MgSO 4) and then concentrated in vacuo. The residue is purified by chromatography, after which the preparation is recrystallized to give the title compound.

Example 9 2- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-vinyl-11,5-acetoxymethyl] pyridine

A solution of 2.81 g (10 mmol) of 2- [4- (2,6,6-trimethylcyclohex-1-enyl] -5-hydroxymethylpyridine, 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) ) 4-dimethylaminopyridine in 150 ml of methylene chloride, stirred at room temperature for 48 hours, then the reaction mixture is filtered and the residue is washed with 50 ml of methylene chloride, the filtrate is then concentrated in vacuo and the residue is purified by chromatography and recrystallized from the title compound. .

Example 10 2- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-ynyl-11-pyridine-5-carboxaldehyde

A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure equalizing addition funnels attached to the drying tubes. The solution is cooled to -60 ° C and then a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride is added dropwise over 5 minutes. Thus, the reaction mixture is stirred at -60 ° C for another 10 minutes. Then, over a period of five minutes, a solution of 2.81 g (10 mmol) of 2- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1] is added to the reaction mixture. -ynyl] -5-hydroxymethylpyridine in 10 ml of methylene chloride. The mixture is stirred for a further 15 minutes and then treated with 5.06 g of 50 (mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. 30 ml of water are added to the mixture and stirring is continued for a further 10 minutes. The organic layer is separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na 2 CO 3 solution and then dried (MgSO 4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography, followed by recrystallization to give the title compound.

Il 90766 17

Example 11 2- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-methyl-5- (1-hydroxypropyl) dyridine

Four ml of 3 molar (12 mmol) ethylmagnesium bromide in ether are placed in a 3-necked flask equipped with a mechanical stirrer, a reflux condenser protected by a drying tube and a pressure equalizing dropping funnel protected by a drying tube. Cool the flask with an ice bath and slowly, with vigorous stirring, add a solution of 2.8 (10 mmol) of 2- (4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1- ynyl] -pyridine-5-carboxaldehyde in 10 ml of dry ether.

The cooling bath is then removed and the mixture is refluxed for 3 hours. The mixture is then cooled in an ice-salt bath, and 5 ml of saturated ammonium chloride solution is added to the mixture. The mixture is stirred for a further hour, then filtered and the residue is washed with two 10 ml portions of ether. The ether solution is then separated, dried (MgSO 4) and the ether removed in vacuo. The residue is then purified by chromatography, after which the preparation is recrystallized to give the title compound.

Example 12 2- [4- (2,6,6-Trimethylcyclohex-1-enyl) -but-3-en-1-methyl-11,5-dimethoxymethyl] twridine

The round-bottomed flask is equipped with a Dean-Stark apparatus and a reflux condenser protected by a drying tube. A mixture of 3.35 g (12 mmol) of 2- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] pyridine-5-carboxaldehyde, 4.80 mg (15 mmol) of anhydrous methanol, 2 mg of p-toluenesulfonic acid monohydrate, and 10 mL of anhydrous benzene are placed in a flask, and the mixture is refluxed under nitrogen until an almost theoretical amount of water accumulates in the Dean-Stark trap. The reaction mixture is cooled to room temperature and extracted successively with 5 ml of 10% sodium hydroxide solution and two 5 ml portions of water, and then dried (MgSO 4). The solution is then filtered and the solvent removed in vacuo. The residue is purified by chromatography and then recrystallized to give the title compound.

li

Claims (8)

A process for the preparation of a pharmaceutically active 4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl-substituted compound of formula (I) AB Jy in which A is pyridyl, furyl or thienyl; and B is -COOH or a pharmaceutically acceptable site thereof or a lower alkyl ester thereof, -CHO, di-lower alkoxymethyl, 1-hydroxy lower alkyl or lower alkyl carbonyloxymethyl, characterized in that a compound of the following formula II is reacted with a compound of the following formula III in the presence of Pd (PQ3) 4 (Q is phenyl) or a similar comb, for example s ** - ZnCl XAB II III in which Formula III A is as defined above, X is halogen, preferably iodine, and B is a protected carboxylic acid, alcohol aldehyde, to obtain a compound of formula I, and possibly transfer a obtained compound of formula I to another compound of formula I. Process according to Claim 1, characterized in that a compound of formula I wherein A is prepared is pyridyl. Process according to claim 1, characterized in that a compound of formula I wherein B is -COOH or a lower alkyl ester, -CHO or -CH2OH or a pharmaceutically acceptable site thereof is prepared. Process according to claim 3, characterized in that the ethyl ester of 6- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] nicotinic acid or 6- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-ene-1-ynyl] nicotinic acid or a pharmaceutically acceptable site thereof. Process according to claim 1, characterized in that a compound of formula I wherein A is prepared is furyl. Process according to Claim 5, characterized in that the ethyl ester of 5- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] furanecarboxylic acid or 5- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-yl] furanecarboxylic acid. Process according to claim 1, characterized in that a compound of formula I wherein A is prepared is thienyl. Process according to claim 1, characterized in that the ethyl ester of 5- [4- (2,6,6-trimethylcyclohex-1-enyl) -but-3-en-1-ynyl] thiophene-2-carboxylic acid or - [4- (2,6,6-trimethylcyclohex-enyl) -but-3-en-l-ynyl] thiophene-2-carboxylic acid.